Potential Effect of Baobab's Polyphenols as Antihyperlipidemic Agents: In Silico Study.

Adansonia digitata L. is an African tree commonly called baobab. This tree is effectively used in traditional medicine to treat cardiovascular disorders. Hyperlipidemia is a well-known cardiovascular risk factor associated with the increased incidence of mortality worldwide. This study aimed to demonstrate the mechanism of baobab polyphenols in the activities of hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and pancreatic lipase as lipid metabolic enzymes. Molecular docking and an incentive for drug design showed that all the polyphenols in baobab bound to the proteins with higher affinity and a lower binding energy compared with simvastatin as the positive control (ΔG: from -5.5 kcal/mol to -6.5 kcal/mol). The same polyphenols exhibited a considerable binding affinity to pancreatic lipase (ΔG: from -7.5 kcal/mol to -9.8 kcal/mol) in comparison with the control and HMG-CoA reductase. Quercetin showed the best docking score from the selected Baobab polyphenols (ΔG = -9.8 kcal/mol). The root mean square deviation (RMSD) results indicated that stable epicatechin and quercetin complexes were demonstrated with HMG-CoA reductase, and other less stable complexes were developed using rutin and chlorogenic acid. Moreover, the analysis of the root mean square fluctuation (RMSF) simulation results was consistent with that of the RMSD. The RMSF value for all the baobab polyphenols, including the crystal control ligand, was kept between 0.80 and 8.00 Å, similarly to simvastatin, and less than 4.8 Å for pancreatic lipase. Chlorogenic acid, quercetin, epicatechin, and rutin had negative ΔG binding scores from highest to lowest. The same ligands displayed more negative ΔG binding scores than those observed in HMG-CoA reductase and crystal control ligand (methoxyundecyl phosphinic acid) in their simulation with pancreatic lipase. In conclusion, baobab polyphenols interact with HMG-CoA reductase and pancreatic lipase to inhibit their substrate binding and block their activity.

Coenzyme biosynthesis in response to precursor availability reveals incorporation of ß-alanine from pantothenate in prototrophic bacteria.

Coenzymes are important for all classes of enzymatic reactions and essential for cellular metabolism. Most coenzymes are synthesized from dedicated precursors, also referred to as vitamins, which prototrophic bacteria can either produce themselves from simpler substrates or take up from the environment. The extent to which prototrophs use supplied vitamins and whether externally available vitamins affect the size of intracellular coenzyme pools and control endogenous vitamin synthesis is currently largely unknown. Here, we studied coenzyme pool sizes and vitamin incorporation into coenzymes during growth on different carbon sources and vitamin supplementation regimes using metabolomics approaches. We found that the model bacterium Escherichia coli incorporated pyridoxal, niacin, and pantothenate into pyridoxal 5'-phosphate, NAD, and coenzyme A (CoA), respectively. In contrast, riboflavin was not taken up and was produced exclusively endogenously. Coenzyme pools were mostly homeostatic and not affected by externally supplied precursors. Remarkably, we found that pantothenate is not incorporated into CoA as such but is first degraded to pantoate and ß-alanine and then rebuilt. This pattern was conserved in various bacterial isolates, suggesting a preference for ß-alanine over pantothenate utilization in CoA synthesis. Finally, we found that the endogenous synthesis of coenzyme precursors remains active when vitamins are supplied, which is consistent with described expression data of genes for enzymes involved in coenzyme biosynthesis under these conditions. Continued production of endogenous coenzymes may ensure rapid synthesis of the mature coenzyme under changing environmental conditions, protect against coenzyme limitation, and explain vitamin availability in naturally oligotrophic environments.

Pantothenate biosynthesis in Toxoplasma gondii tachyzoites is not a drug target.

Toxoplasma gondii is a pervasive apicomplexan parasite that can cause severe disease and death in immunocompromised individuals and the developing foetus. The treatment of toxoplasmosis often leads to serious side effects and novel drugs and drug targets are therefore actively sought. In 2014, Mageed and colleagues suggested that the T. gondii pantothenate synthetase, the enzyme responsible for the synthesis of the vitamin B5 (pantothenate), the precursor of the important cofactor, coenzyme A, is a good drug target. Their conclusion was based on the ability of potent inhibitors of the M. tuberculosis pantothenate synthetase to inhibit the proliferation of T. gondii tachyzoites. They also reported that the inhibitory effect of the compounds could be antagonised by supplementing the medium with pantothenate, supporting their conclusion that the compounds were acting on the intended target. Contrary to these observations, we find that compound SW314, one of the compounds used in the Mageed et al. study and previously shown to be active against M. tuberculosis pantothenate synthetase in vitro, is inactive against the T. gondii pantothenate synthetase and does not inhibit tachyzoite proliferation, despite gaining access into the parasite in situ. Furthermore, we validate the recent observation that the pantothenate synthetase gene in T. gondii can be disrupted without detrimental effect to the survival of the tachyzoite-stage parasite in the presence or absence of extracellular pantothenate. We conclude that the T. gondii pantothenate synthetase is not essential during the tachyzoite stage of the parasite and it is therefore not a target for drug discovery against T. gondii tachyzoites.

Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency.

Early-onset long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency is a fatty acid ß-oxidation disorder with a poor prognosis. Triheptanoin, an anaplerotic oil with odd-chain fatty acids can improve the disease course. The female patient presented here was diagnosed at the age of 4 months, and treatment was started as fat restriction, frequent feeding, and standard medium-chain triglyceride supplementation. In follow-up, she had frequent rhabdomyolysis episodes (∼8 per year). At the age of six, she had 13 episodes in 6 months, and triheptanoin was started as part of a compassionate use program. Following unrelated hospital stays due to multisystem inflammatory syndrome in children and a bloodstream infection, she had only 3 rhabdomyolysis episodes, and hospitalized days decreased from 73 to 11 during her first year with triheptanoin. Triheptanoin drastically decreased the frequency and severity of rhabdomyolysis, but progression of retinopathy was not altered.

Vitamin B5, a coenzyme A precursor, rescues TANGO2 deficiency disease-associated defects in Drosophila and human cells.

Mutations in the Transport and Golgi Organization 2 (TANGO2) gene are associated with intellectual deficit, neurodevelopmental delay and regression. Individuals can also present with an acute metabolic crisis that includes rhabdomyolysis, cardiomyopathy, and cardiac arrhythmias, the latter of which are potentially lethal. While preventing metabolic crises has the potential to reduce mortality, no treatments currently exist for this condition. The function of TANGO2 remains unknown but is suspected to be involved in some aspect of lipid metabolism. Here, we describe a model of TANGO2-related disease in the fruit fly Drosophila melanogaster that recapitulates crucial disease traits. Pairing a new fly model with human cells, we examined the effects of vitamin B5, a coenzyme A (CoA) precursor, on alleviating the cellular and organismal defects associated with TANGO2 deficiency. We demonstrate that vitamin B5 specifically improves multiple defects associated with TANGO2 loss-of-function in Drosophila and rescues membrane trafficking defects in human cells. We also observed a partial rescue of one of the fly defects by vitamin B3, though to a lesser extent than vitamin B5. Our data suggest that a B complex supplement containing vitamin B5/pantothenate may have therapeutic benefits in individuals with TANGO2-deficiency disease. Possible mechanisms for the rescue are discussed that may include restoration of lipid homeostasis.

Selenium and vitamin B6 cosupplementation improves dyslipidemia and fatty liver syndrome by SIRT1/SREBP-1c pathway in hyperlipidemic Sprague-Dawley rats induced by high-fat diet.

Previously, our group found that the dietary trace mineral element selenium and vitamin B6 (VitB6) alone was involved in lipid metabolism. However, the effects of selenium combined with VitB6 on hyperlipidemia and lipid metabolism have not been reported until now. We hypothesized that selenium and VitB6 cosupplementation would alleviate the hyperlipidemic and hepatic dysfunction and with minimum side effects in a Sprague-Dawley rat model of hyperlipidemia induced by a high-fat diet. Our results showed that selenium combined with VitB6 could improve dyslipidemia and displayed better in vivo hypocholesterolemic abilities at early intervention. Moreover, cosupplementation reduced atherogenic indexes (atherogenic index and atherogenic index of plasm) and the ratio of ApoB/ApoA1. The liver function index aspartate aminotransferase in serum was reduced, as was and total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol in liver. The intervention also increased the levels of ApoA1 in serum and high-density lipoprotein cholesterol of liver. In addition, the combination of selenium and VitB6 decreased liver lipid deposition and alleviated steatosis, reduced adipocyte size of white adipose tissue, increased the activities of hepatic lipase and total lipase and the hepatic 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMGR) level, decreased the hepatic mRNA transcription of lipogenic and regulatory genes including Srebf1 and downstream fat synthesis-related enzymes (Acc and Fasn) and cholesterol synthesis speed limiting enzyme Hmgr, increased the mRNA abundance of Lcat and Cyp7a1, increased the protein expression of SIRT1 and PPARα, and up-regulated the protein expression of sterol regulatory element-binding protein 1c in the livers of hyperlipidemia rats. We first demonstrated that oral selenium and VitB6 cosupplementation exerted synergism in lowering blood and liver lipid profiles and antiatherosclerotic effects in hyperlipidemic rats by reducing endogenous cholesterol and lipid synthesis, enhancing the transport of cholesterol to hepatocytes and promoting fatty acid beta oxidation.

Anti-inflammatory, cytotoxicity and antilipidemic properties: novel bioactivities of true cinnamon (Cinnamomum zeylanicum Blume) leaf.

BACKGROUND: The leaf of Ceylon cinnamon (true cinnamon) is traditionally claimed for a variety of health benefits. However, reported scientific information is scanty and needs urgent attention for value addition. METHODS: Ethanolic (95%) and Dichloromethane:Methanol (DM, 1:1 v/v) leaf extracts of Ceylon cinnamon were evaluated for a range of medically important bioactivities namely anti-inflammatory [nitric oxide scavenging activity (NOSA), superoxide scavenging activity (SCA), COX1 and COX2 inhibition], growth inhibition & cytotoxicity against MCF7, HePG2 and AN3CA carcinoma cell lines, glutathionase-S-transferase (GST) inhibition and antilipidemic (anti-HMG-CoA reductase, anti-lipase, anti-cholesterol esterase, and cholesterol micellization inhibition) properties in vitro (n = 3). Further, a range of bioactive compounds in both leaf extracts was also quantified (n = 3). RESULTS: Both leaf extracts had all the investigated bioactive compounds and possessed moderately potent bioactivities compared to the reference drugs used in the study. Ethanolic leaf extract (ELE) exhibited the highest activities (IC50: µg/mL) for NOSA (40.26 ± 0.52), SCA (696.24 ± 40.02), cholesterol esterase inhibition (110.19 ± 1.55), cholesterol micellization inhibition (616.69 ± 7.09), GST inhibition (403.78 ± 2.70) and growth inhibition (GI50: 144.84 ± 1.59-269.00 ± 0.51) & cytotoxicity (LC50: 355.44 ± 9.38-717.71 ± 23.69) against studied cancer cell lines. In contrast, COX1 & COX2 (IC50: 6.62 ± 0.85 and 44.91 ± 3.06 µg/mL) and HMG-CoA reductase & lipase inhibitory activities (36.72 ± 4.74 and 19.71 ± 0.97% inhibition at 200 and 600 µg/mL) were highest in DM extract. ELE also showed the highest quantities (0.81 ± 0.06-104.38 ± 1.79) of tested compounds (mg/g extract) where eugenol was the highest and gallic acid was the lowest among quantified. CONCLUSION: Both leaf extracts of Ceylon cinnamon had all the tested bioactive compounds and possess all the investigated bioactivities. This is the 1st study to report all the investigated bioactivities of the leaf of Ceylon Cinnamon.

The ZmMYB84-ZmPKSB regulatory module controls male fertility through modulating anther cuticle-pollen exine trade-off in maize anthers.

Anther cuticle and pollen exine are two crucial lipid layers that ensure normal pollen development and pollen-stigma interaction for successful fertilization and seed production in plants. Their formation processes share certain common pathways of lipid biosynthesis and transport across four anther wall layers. However, molecular mechanism underlying a trade-off of lipid-metabolic products to promote the proper formation of the two lipid layers remains elusive. Here, we identified and characterized a maize male-sterility mutant pksb, which displayed denser anther cuticle but thinner pollen exine as well as delayed tapetal degeneration compared with its wild type. Based on map-based cloning and CRISPR/Cas9 mutagenesis, we found that the causal gene (ZmPKSB) of pksb mutant encoded an endoplasmic reticulum (ER)-localized polyketide synthase (PKS) with catalytic activities to malonyl-CoA and midchain-fatty acyl-CoA to generate triketide and tetraketide α-pyrone. A conserved catalytic triad (C171, H320 and N353) was essential for its enzymatic activity. ZmPKSB was specifically expressed in maize anthers from stages S8b to S9-10 with its peak at S9 and was directly activated by a transcription factor ZmMYB84. Moreover, loss function of ZmMYB84 resulted in denser anther cuticle but thinner pollen exine similar to the pksb mutant. The ZmMYB84-ZmPKSB regulatory module controlled a trade-off between anther cuticle and pollen exine formation by altering expression of a series of genes related to biosynthesis and transport of sporopollenin, cutin and wax. These findings provide new insights into the fine-tuning regulation of lipid-metabolic balance to precisely promote anther cuticle and pollen exine formation in plants.

Network pharmacology combined with metabolomics reveals the mechanism of Fuzi decoction against chronic heart failure in rats.

Chronic heart failure (CHF) is the end stage of many severe heart diseases. Fuzi decoction (FZD) originates from Zhang Zhongjing's Treatise on Febrile Diseases and is widely used in the treatment of CHF in the clinic, but the potential mechanism of FZD in CHF is unclear. In this study, an integrated approach combining network pharmacology and metabolomics was adopted to explore the mechanism of FZD in CHF. Network pharmacological studies indicated that the most significant signaling pathway was the HIF-1 signaling pathway. Untargeted metabolomics indicated abnormalities in serum metabolism in CHF rats, and FZD treatment significantly improved the metabolic abnormalities and altered the levels of 30 metabolites. A pathway enrichment analysis showed that FZD was mainly involved in glycine, serine and threonine metabolism, aminoacyl-tRNA biosynthesis, ß-alanine metabolism, pantothenate and CoA biosynthesis, glyoxylate and dicarboxylate metabolism and other metabolic pathways. A correlation analysis showed that pyruvate and lactate were strongly correlated with the heart failure index, and a targeted metabolomics study showed that FZD restored the balance of the pyruvate-lactate axis that was disrupted due to CHF. Therefore, the mechanism of FZD against CHF may be related to regulate HIF-1 signaling pathway, pyruvate-lactate axis and glycine, serine and threonine metabolism.

The Combined Escherichia coli Nissle 1917 and Tryptophan Treatment Modulates Immune and Metabolome Responses to Human Rotavirus Infection in a Human Infant Fecal Microbiota-Transplanted Malnourished Gnotobiotic Pig Model.

Human rotavirus (HRV) is a major cause of childhood diarrhea in developing countries where widespread malnutrition contributes to the decreased oral vaccine efficacy and increased prevalence of other enteric infections, which are major concerns for global health. Neonatal gnotobiotic (Gn) piglets closely resemble human infants in their anatomy, physiology, and outbred status, providing a unique model to investigate malnutrition, supplementations, and HRV infection. To understand the molecular signatures associated with immune enhancement and reduced diarrheal severity by Escherichia coli Nissle 1917 (EcN) and tryptophan (TRP), immunological responses and global nontargeted metabolomics and lipidomics approaches were investigated on the plasma and fecal contents of malnourished pigs transplanted with human infant fecal microbiota and infected with virulent (Vir) HRV. Overall, EcN + TRP combined (rather than individual supplement action) promoted greater and balanced immunoregulatory/immunostimulatory responses associated with greater protection against HRV infection and disease in malnourished humanized piglets. Moreover, EcN + TRP treatment upregulated the production of several metabolites with immunoregulatory/immunostimulatory properties: amino acids (N-acetylserotonin, methylacetoacetyl-CoA), lipids (gamma-butyrobetaine, eicosanoids, cholesterol-sulfate, sphinganine/phytosphingosine, leukotriene), organic compound (biliverdin), benzenoids (gentisic acid, aminobenzoic acid), and nucleotides (hypoxathine/inosine/xanthine, cytidine-5'-monophosphate). Additionally, the levels of several proinflammatory metabolites of organic compounds (adenosylhomocysteine, phenylacetylglycine, urobilinogen/coproporphyrinogen) and amino acid (phenylalanine) were reduced following EcN + TRP treatment. These results suggest that the EcN + TRP effects on reducing HRV diarrhea in neonatal Gn pigs were at least in part due to altered metabolites, those involved in lipid, amino acid, benzenoids, organic compounds, and nucleotide metabolism. Identification of these important mechanisms of EcN/TRP prevention of HRV diarrhea provides novel targets for therapeutics development. IMPORTANCE Human rotavirus (HRV) is the most common cause of viral gastroenteritis in children, especially in developing countries, where the efficacy of oral HRV vaccines is reduced. Escherichia coli Nissle 1917 (EcN) is used to treat enteric infections and ulcerative colitis while tryptophan (TRP) is a biomarker of malnutrition, and its supplementation can alleviate intestinal inflammation and normalize intestinal microbiota in malnourished hosts. Supplementation of EcN + TRP to malnourished humanized gnotobiotic piglets enhanced immune responses and resulted in greater protection against HRV infection and diarrhea. Moreover, EcN + TRP supplementation increased the levels of immunoregulatory/immunostimulatory metabolites while decreasing the production of proinflammatory metabolites in plasma and fecal samples. Profiling of immunoregulatory and proinflammatory biomarkers associated with HRV perturbations will aid in the identification of treatments against HRV and other enteric diseases in malnourished children.

TFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis.

Fatty liver is a highly heterogenous condition driven by various pathogenic factors in addition to the severity of steatosis. Protein insufficiency has been causally linked to fatty liver with incompletely defined mechanisms. Here we report that fatty liver is a sulfur amino acid insufficient state that promotes metabolic inflexibility via limiting coenzyme A availability. We demonstrate that the nutrient-sensing transcriptional factor EB synergistically stimulates lysosome proteolysis and methionine adenosyltransferase to increase cysteine pool that drives the production of coenzyme A and glutathione, which support metabolic adaptation and antioxidant defense during increased lipid influx. Intriguingly, mice consuming an isocaloric protein-deficient Western diet exhibit selective hepatic cysteine, coenzyme A and glutathione deficiency and acylcarnitine accumulation, which are reversed by cystine supplementation without normalizing dietary protein intake. These findings support a pathogenic link of dysregulated sulfur amino acid metabolism to metabolic inflexibility that underlies both overnutrition and protein malnutrition-associated fatty liver development.

Mori fructus aqueous extracts attenuate carbon tetrachloride-induced renal injury via the Nrf2 pathway and intestinal flora.

Mori fructus aqueous extracts (MFAEs) have been used as a traditional Chinese medicine for thousands of years with the function of strengthening the liver and tonifying the kidney. However, its inner mechanism to alleviative renal injury is unclear. To investigate the attenuation of MFAEs on nephrotoxicity and uncover its potential molecular mechanism, we established a nephrotoxicity model induced by carbon tetrachloride (CCl4). The mice were randomly divided into control group, CCl4 model group (10% CCl4), CCl4 + low and high MFAEs groups (10% CCl4 + 100 mg/kg and 200 mg/kg MFAEs). We found that MFAEs decreased the kidney index of mice, restored the pathological changes of renal structure induced by CCl4, reduced cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (Kim-1) blood urea nitrogen and creatinine contents in serum, promoted the nuclear transportation of Nrf2 (nuclear factor erythroid derived 2 like 2), elevated the expression of HO-1 (heme oxygenase 1), GPX4 (glutathione peroxidase 4), SLC7A11 (solute carrier family 7 member 11), ZO-1 (zonula occludens-1) and Occludin, suppressed the expression of Keap1 (kelch-like ECH-associated protein 1), HMGB1 (High Mobility Group Protein 1), ACSL4 (acyl-CoA synthetase long chain family member 4) and TXNIP (thioredoxin interacting protein), upregulated the flora of Akkermansia, Anaerotruncus, Clostridium_sensu_stricto, Ihubacter, Alcaligenes, Dysosmobacter, and downregulated the flora of Clostridium_XlVa, Helicobacter, Paramuribaculum. Overlapped with Disbiome database, Clostridium_XlVa, Akkermansia and Anaerotruncus may be the potential genera treated with renal injury. It indicated that MFAEs could ameliorate kidney injury caused by CCl4 via Nrf2 signaling.

In silico identification of bacterial seaweed-degrading bioplastic producers.

There is an urgent need to replace petroleum-based plastic with bio-based and biodegradable alternatives. Polyhydroxyalkanoates (PHAs) are attractive prospective replacements that exhibit desirable mechanical properties and are recyclable and biodegradable in terrestrial and marine environments. However, the production costs today still limit the economic sustainability of the PHA industry. Seaweed cultivation represents an opportunity for carbon capture, while also supplying a sustainable photosynthetic feedstock for PHA production. We mined existing gene and protein databases to identify bacteria able to grow and produce PHAs using seaweed-derived carbohydrates as substrates. There were no significant relationships between the genes involved in the deconstruction of algae polysaccharides and PHA production, with poor to negative correlations and diffused clustering suggesting evolutionary compartmentalism. We identified 2 987 bacterial candidates spanning 40 taxonomic families predominantly within Alphaproteobacteria, Gammaproteobacteria and Burkholderiales with enriched seaweed-degrading capacity that also harbour PHA synthesis potential. These included highly promising candidates with specialist and generalist specificities, including Alteromonas, Aquisphaera, Azotobacter, Bacillus, Caulobacter, Cellvibrionaceae, Duganella, Janthinobacterium, Massilia, Oxalobacteraceae, Parvularcula, Pirellulaceae, Pseudomonas, Rhizobacter, Rhodanobacter, Simiduia, Sphingobium, Sphingomonadaceae, Sphingomonas, Stieleria, Vibrio and Xanthomonas. In this enriched subset, the family-level densities of genes targeting green macroalgae polysaccharides were considerably higher (n=231.6±68.5) than enzymes targeting brown (n=65.34±13.12) and red (n=30.5±10.72) polysaccharides. Within these organisms, an abundance of FabG genes was observed, suggesting that the fatty acid de novo synthesis pathway supplies (R)-3-hydroxyacyl-CoA or 3-hydroxybutyryl-CoA from core metabolic processes and is the predominant mechanism of PHA production in these organisms. Our results facilitate extending seaweed biomass valorization in the context of consolidated biorefining for the production of bioplastics.

GCTOF-MS Combined LC-QTRAP-MS/MS Reveals Metabolic Difference Between Osteoarthritis and Osteoporotic Osteoarthritis and the Intervention Effect of Erxian Decoction.

Purpose: OP and OA are chronic bone diseases with high incidence in the middle-aged and elderly populations. The latest research shows that the pathological environment of OP may be involved in the aggravation of the pathological process of OA, and the pathological state of OP plays an important role in the aggravation of OA pathology. EXD is a traditional Chinese medicine decoction that has been used to treat osteoporosis. Therefore, we further study whether OA will be aggravated in the OP environment and whether EXD can alleviate OA by intervening in the OP environment. The purpose of this study was to analyze the effect of OP on OA metabolites by using metabolomic methods and to explore the intervention mechanism of EXD on osteoporotic OA. Method: Thirty-two SD rats were randomly divided into normal group, OA group, OP-OA group, and EXD group. EXD was administered by gavage. Histopathological evaluation of cartilage tissue was performed using Saffron fast green and HE staining. Western blot and qRT-PCR were used to detect the expression levels of chondrogenesis genes SOX9, COL2A1, and COMP in cartilage tissue. GC-TOFMS and LC-QTRAP-MS/MS metabolomics methods were used to analyze the changes of metabolites in serum samples of rats in each group. Result: The slice results showed that the cartilage damage in the OP-OA group was more serious than that in the OA group, which was significantly relieved after EXD intervention, indicating that the cartilage damage in the OP-OA group was more severe than that in the OA group and further reduced the protein and gene expressions of cartilage markers SOX9, COL2A1, and COMP. Thirty-seven substances were identified, and gentiopicroside, emodin, quercetin, and diosmetin were analyzed as possible active components of EXD. EXD treatment significantly reduced cartilage damage and reversed the expression of these markers. Metabolomics showed that EXD attenuated cartilage destruction by modulating the expression of cystine, chenodeoxycholate, and D-Turanose, involving glycolysis/gluconeogenesis, pantothenate, and CoA biosynthesis metabolic pathways. Conclusion: The OP environment may promote the progression of OA through metabolic factors. The benign intervention of EXD in osteoporotic OA involves cystine, chenodeoxycholate, and D-Turanose, and their associated glycolysis/gluconeogenesis, pantothenate, and CoA biosynthesis metabolic pathways. Therefore, we have a deep understanding of the metabolic-related intervention of EXD in osteoporotic OA and are eager to better understand the mechanism of multi-targeted intervention of EXD in bone metabolic lesions.

Shenmai Injection Attenuates Myocardial Ischemia/Reperfusion Injury by Targeting Nrf2/GPX4 Signalling-Mediated Ferroptosis.

OBJECTIVE: To examine the effect of Shenmai Injection (SMJ) on ferroptosis during myocardial ischemia reperfusion (I/R) injury in rats and the underlying mechanism. METHODS: A total of 120 SPF-grade adult male SD rats, weighing 220-250 g were randomly divided into different groups according to a random number table. Myocardial I/R model was established by occluding the left anterior descending artery for 30 min followed by 120 min of reperfusion. SMJ was injected intraperitoneally at the onset of 120 min of reperfusion, and erastin (an agonist of ferroptosis), ferrostatin-1 (Fer-1, an inhibitor of ferroptosis) and ML385 (an inhibitor of nuclear factor erythroid-2 related factor 2 (Nrf2)) were administered intraperitoneally separately 30 min before myocardial ischemia as different pretreatments. Cardiac function before ischemia, after ischemia and after reperfusion was analysed. Pathological changes in the myocardium and the ultrastructure of cardiomyocytes were observed, and the myocardial infarction area was measured. Additionally, the concentration of Fe2+ in heart tissues and the levels of creatine kinase-MB (CK-MB), troponin I (cTnl), malondialdehyde (MDA) and superoxide dismutase (SOD) in serum were measured using assay kits, and the expressions of Nrf2, glutathione peroxidase 4 (GPX4) and acyl-CoA synthetase long-chain family member 4 (ACSL4) were examined by Western blot. RESULTS: Compared with the sham group, I/R significantly injured heart tissues, as evidenced by the disordered, ruptured and oedematous myocardial fibres; the increases in infarct size, serum CK-MB, cTnI and MDA levels, and myocardial Fe2+ concentrations; and the decreases in SOD activity (P<0.05). These results were accompanied by ultrastructural alterations to the mitochondria, increased expression of ACSL4 and inhibited the activation of Nrf2/GPX4 signalling (P<0.05). Compared with I/R group, pretreatment with 9 mL/kg SMJ and 2 mg/kg Fer-1 significantly reduced myocardial I/R injury, Fe2+ concentrations and ACSL4 expression and attenuated mitochondrial impairment, while 14 mg/kg erastin exacerbated myocardial I/R injury (P<0.05). In addition, cardioprotection provided by 9 mL/kg SMJ was completely reversed by ML385, as evidenced by the increased myocardial infarct size, CK-MB, cTnI, MDA and Fe2+ concentrations, and the decreased SOD activity (P<0.05). CONCLUSIONS: Ferroptosis is involved in myocardial I/R injury. Pretreatment with SMJ alleviated myocardial I/R injury by activating Nrf2/GPX4 signalling-mediated ferroptosis, thereby providing a strategy for the prevention and treatment of ischemic heart diseases.

Turanecio hypochionaeus: Determination of Its Polyphenol Contents, and Bioactivities Potential Assisted with in Silico Studies.

The aim of this study was to identify and quantify the phenolic composition of Turanecio hypochionaeus Bosse and determine the anti-urease, anti-lipase, antidiabetic, anti-melanogenesis, antibacterial, and anti-Alzheimer properties. IC50 results for all enzymes were obtained between 0.234-116.50 µg/mL and this plant inhibited HMG_CoA R and glucosidase enzymes more with IC50 values of 0.234 and 116.50 µg/mL, respectively. Among the 11 secondary metabolites identified in T. hypochionaeus extract, chlorogenic acid 255.459±1.17 µg g-1 ), benzoic acid (56.251±1.98 µg g-1 ), and catechin (29.029±0.27 µg g-1 ) were determined as the most abundant phenolic compounds. According to the results of the tested microorganisms, the plant extracts showed antimicrobial and antifungal properties in a dose-dependent manner. In molecular docking study, the interactions of active compounds extracted from Turanecio hypochionaeus plant and showing activity against diverse metabolic enzymes were examined. The most active compound 1, (chlorogenic acid) has -12.80, -12.80, -12.60 and -12.00 kcal/mol binding energy value against HMG_CoA R, and α-amylase, α-glucosidase, and lipase, respectively.

Supplementation with Ginseng, Lilii Bulbus, and Poria induces alterations in the serum metabolic profile of healthy adults.

The preventive and therapeutic effects of herbal supplementation containing Ginseng, Lilii Bulbus, and Poria (GLP) on inflammation and oxidative stress in healthy adults have been demonstrated in our previous studies. However, the underlying mechanisms of organism protection by GLP remain unclarified, and few studies have used metabolomics to investigate comprehensive changes before and after GLP supplementation. Based on previous research, we conducted a placebo-controlled trial among 82 healthy adults in Wuhan, China, using a metabolomics approach with ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) and multivariate statistical methods to analyze serum metabolite alterations in participants before and after GLP supplementation. Furthermore, 14 discriminant metabolites related to lipid metabolism, inflammation and oxidative stress, energy metabolism, and coenzyme A metabolism were significantly different between the before- and after-GLP groups (P < 0.0001). Nine metabolites were significantly decreased in the serum samples from the after-GLP group compared with the before-GLP group, while five metabolites were significantly increased. These metabolites could be critical components associated with the anti-inflammatory, antioxidant, and hypolipidemic activities of GLP, indicating the potential complementary role of GLP supplements in the primary prevention of dysfunctional metabolism caused by potential diseases such as cardiovascular disease. This study provides a valuable reference for cardiovascular health protection and disease prevention.

Phytochemical and biological studies on rare and endangered plants endemic to China. Part XXV. Structurally diverse triterpenoids and diterpenoids from two endangered Pinaceae plants endemic to the Chinese Qinling Mountains and their bioactivities.

A joint phytochemical investigation on the MeOH extracts of the twigs and needles of two endangered Pinaceae plants endemic to the Chinese Qinling Mountains, Picea neoveitchii (an evergreen spruce) and Larix potaninii var. chinensis (a deciduous larch), led to the isolation and characterization of 34 and 24 structurally diverse terpenoids, respectively. Among them, seven are previously undescribed, including a picane-type [i.e., 14(13 â†’ 12)abeo-12αH-serratane] (neoveitchin A) and a serratane-type (neoveitchin B) triterpenoids, and an abietane-type (neoveitchin C) as well as four labdane-type (potalarxins A-D) diterpenoids. Their structures and absolute configurations were established by extensive spectroscopic methods and/or X-ray diffraction analyses. All isolates were evaluated for their inhibitory activities against the human protein tyrosine phosphatase 1B (PTP1B). Serrat-14-en-3α,21ß-diol, betulinic acid, 3ß-hydroxy-11-ursen-13(28)-olide, ursolic acid, and oleanolic acid were found to have considerable inhibitory effects against PTP1B, with IC50 values ranging from 1.1 to 18.1 µM. The interactions of the bioactive triterpenoids with PTP1B were thereafter performed by employing molecular docking studies. In addition, 7-oxo-dehydroabietic acid (an abietane-type diterpenoid) and mangiferonic acid (a cycloartane-type triterpenoid) inhibited acetyl-coenzyme A carboxylase 1 (ACC1), with IC50 values of 3.4 and 6.6 µM, respectively.

Characterization of an (R)-specific enoyl-CoA hydratase from Streptomyces sp. strain CFMR 7: A metabolic tool for enhancing the production of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate).

Poly[(R)-3-hydroxybutyrate-co-(R)-3-hydroxyhexanoate] [P(3HB-co-3HHx)] has a high potential to serve as a commercial bioplastic due to its biodegradability, thermoplastic and mechanical properties. The properties of this copolymer are greatly affected by the composition of 3HHx monomer. One of the most efficient ways to modulate the composition of 3HHx monomer in P(3HB-co-3HHx) is by manipulating the (R)-3HHx-CoA monomer supply. In this study, a new (R)-specific enoyl-CoA hydratase originating from a non-PHA producer, Streptomyces sp. strain CFMR 7 (PhaJSs), was characterized and found to be effective in supplying 3HHx monomer during in vivo production of P(3HB-co-3HHx) copolymer. The P(3HB-co-3HHx) copolymer produced from the Cupriavidus necator transformant that harbors phaJSs, PHB-4/pBBR1-CBP-M-CPF4JSs, showed enhanced 3HHx incorporation of up to 11 mol% without affecting the P(3HB-co-3HHx) production when palm oil was used as the carbon source. In addition, both kcat and kcat/Km of PhaJSs were higher toward the C6 than the shorter C4 substrates, underscoring the preference for 3-hydroxyhexanoyl-CoA. These results suggest that PhaJSs has a significant ability to supply 3HHx monomers for PHA biosynthesis via ß-oxidation and can be applied for metabolic engineering of robust PHA-producing strains.

Cinnamon extract improves abnormalities in glucose tolerance by decreasing Acyl-CoA synthetase long-chain family 1 expression in adipocytes.

We previously demonstrated that cinnamon extract (CE) alleviates streptozotocin-induced type 1 diabetes in rats. The present study aimed to elucidate the detailed molecular target of cinnamon in cultured adipocytes and epididymal adipose tissue of type 2 diabetes model mice. Two-dimensional gel electrophoresis was employed to determine the molecular target of cinnamon in adipocytes. The function of Acyl-CoA synthetase long-chain family-1 (ACSL1), a molecular target of cinnamon that was identified in this study, was further investigated in 3T3-L1 adipocytes using specific inhibitors. Type 2 diabetes model mice (KK-Ay/TaJcl) were used to investigate the effect of CE on glucose tolerance, ACSL1 expression, and related signal molecules in vivo. CE decreased ACSL1 mRNA and protein expression in 3T3-L1 adipocytes but increased glucose uptake and AMPK signaling activation; moreover, a similar effect was observed with an ACSL1 inhibitor. CE improved glucose tolerance and downregulated ACSL1 in mice adipose tissue in vivo. ACSL1 was demonstrated as a molecular target of CE in type 2 diabetes both in a cell culture system and diabetic mouse model.